Journal of Molecular Modeling

, Volume 19, Issue 3, pp 1179–1194 | Cite as

In vitro inhibitory profile of NDGA against AChE and its in silico structural modifications based on ADME profile

  • Chandran Remya
  • Kalarickal Vijayan Dileep
  • Ignatius Tintu
  • Elessery Jayadevi Variyar
  • Chittalakkottu Sadasivan
Original Paper


Acetylcholinesterase (AChE) inhibitors are currently in focus for the pharmacotherapy of Alzheimer’s disease (AD). These inhibitors increase the level of acetylcholine in the brain and facilitate cholinergic neurotransmission. AChE inhibitors such as rivastigmine, galantamine, physostigmine and huperzine are obtained from plants, indicating that plants can serve as a potential source for novel AChE inhibitors. We have performed a virtual screening of diverse natural products with distinct chemical structure against AChE. NDGA was one among the top scored compounds and was selected for enzyme kinetic studies. The IC50 of NDGA on AChE was 46.2 μM. However, NDGA showed very poor central nervous system (CNS) activity and blood–brain barrier (BBB) penetration. In silico structural modification on NDGA was carried out in order to obtain derivatives with better CNS activity as well as BBB penetration. The studies revealed that some of the designed compounds can be used as lead molecules for the development of drugs against AD


Inhibitory activity of NDGA against AChE


Acetylcholinesterase NDGA ADME CNS activity Induced fit docking 



The authors gratefully acknowledge the use of computational facilities provided by Bioinformatics Infrastructure Facility (supported by DBT, Government of India) at Kannur University and BIOGENE cluster, Bioinformatics Resources and Application Facility at C-DAC (Center for Development of Advanced Computing) Pune, India.


  1. 1.
    Selkoe DJ, Schenk D (2003) Alzheimer’s disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol 43:545–584CrossRefGoogle Scholar
  2. 2.
    Schliebs R (2005) Basal forebrain cholinergic dysfunction in Alzheimer’s disease–interrelationship with beta-amyloid, inflammation and neurotrophin signaling. Neurochem Res 30:895–908CrossRefGoogle Scholar
  3. 3.
    Goedert M, Spillantini MG (2006) A century of Alzheimer’s disease. Science 314:777–781CrossRefGoogle Scholar
  4. 4.
    Luttmann E, Linnemann E, Fels G (2002) Galantamine as bis-functional ligand for the acetylcholinesterase. J Mol Model 8:208–216CrossRefGoogle Scholar
  5. 5.
    Schrattenholz A, Pereira EF, Roth U, Weber KH, Albuquerque EX, Maelicke A (1996) Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands. Mol Pharmacol 49:1–6Google Scholar
  6. 6.
    Coyle JT, Geerts H, Sorra K, Amatniek J (2007) Beyond in vitro data: a review of in vivo evidence regarding the allosteric potentiating effect of galantamine on nicotinic acetylcholine receptors in Alzheimer’s neuropathology. J Alzheimers Dis 11:491–507Google Scholar
  7. 7.
    Reyes AE, Chacon MA, Dinamarca MC, Cerpa W, Morgan C, Inestrosa NC (2004) Acetylcholinesterase—Abeta complexes are more toxic than Abeta fibrils in rat hippocampus: effect on rat beta-amyloid aggregation, laminin expression, reactive astrocytosis, and neuronal cell loss. Am J Pathol 164:2163–2174CrossRefGoogle Scholar
  8. 8.
    Castro A, Martinez A (2006) Targeting beta-amyloid pathogenesis through acetylcholinesterase inhibitors. Curr Pharm Des 12:4377–4387CrossRefGoogle Scholar
  9. 9.
    Kasa P, Papp H, Kasa P Jr, Torok I (2000) Donepezil dose-dependently inhibits acetylcholinesterase activity in various areas and in the presynaptic cholinergic and the postsynaptic cholinoceptive enzyme-positive structures in the human and rat brain. Neuroscience 101:89–100CrossRefGoogle Scholar
  10. 10.
    Kurz A (1998) The therapeutic potential of tacrine. J Neural Transm Suppl 54:295–299Google Scholar
  11. 11.
    Sugimoto H (2001) Donepezil hydrochloride: a treatment drug for Alzheimer’s disease. Chem Rec 1(1):63–73CrossRefGoogle Scholar
  12. 12.
    Zarotsky V, Sramek JJ, Cutler NR (2003) Galantamine hydrobromide: an agent for alzheimer’s disease. Am J Health Syst Pharm 60:446–452Google Scholar
  13. 13.
    Jann MW (2000) Rivastigmine, a new- generation cholinesterase inhibitor for the treatment of Alzheimer’s disease. Pharmacotherapy 20(1):1–12CrossRefGoogle Scholar
  14. 14.
    Francis PT, Nordberg A, Arnold SE (2005) A preclinical view of cholinesterase inhibitors in neuroprotection: do they provide more than symptomatic benefits in Alzheimer’s disease? Trends Pharmacol Sci 26:104–111CrossRefGoogle Scholar
  15. 15.
    Wang YE, Yue DX, Tang XC (1986) Anticholinesterase activity of huperzine A. Acta pharmacol Sin 7:110–113Google Scholar
  16. 16.
    Barak D, Ordentlich A, Stein D, Yu QS, Greig NH, Shafferman A (2009) Accommodation of physostigmine and its analogs by acetylcholinesterase is dominated by hydrophobic interactions. Biochem J 417(1):213–222CrossRefGoogle Scholar
  17. 17.
    Arteaga S, Andrade-Cetto A, Cardenas R (2005) Larrea tridentate (creosote bush) an abundant palnt of Mexican and US-american desert and its metabolite nordihydroguairetic acid. J Ethnopharmol 98(3):231–239CrossRefGoogle Scholar
  18. 18.
    Oliveto EP (1972) Nordihydroguaiaretic acid. A naturally occurring antioxidant. Chem Ind 17:677–679Google Scholar
  19. 19.
    Noor R, Mittal S, Iqbal J (2002) Superoxide dismutase-applications and relevance to human diseases. Med Sci Monit 8:RA210–RA215Google Scholar
  20. 20.
    Guzman-Beltran S, Espada S, Orozco-Ibarra M, Pedraza-Chaverri J, Cuadrado A (2008) Nordihydroguaiaretic acid activates the antioxidant pathway Nrf2/HO-1 and protects cerebellargranule neurons against oxidative stress. Neurosci Lett 447:167–171CrossRefGoogle Scholar
  21. 21.
    Goodman Y, Steiner MR, Steiner SM, Mattson MP (1994) Nordihydroguaiaretic acid protects hippocampal neurons against amyloid beta-peptide toxicity, and attenuates free radical and calcium accumulation. Brain Res 654:171–176CrossRefGoogle Scholar
  22. 22.
    Rothman SM, Yamada KA, Lancaster N (1993) Nordihydroguaiaretic acid attenuates NMDA neurotoxicity—action beyond the receptor. Neuropharmacology 32:1279–1288CrossRefGoogle Scholar
  23. 23.
    Boston-Howes W, Williams EO, Bogush A, Scolere M, Pasinelli P, Trotti D (2008) Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: therapeutic implications for amyotrophic lateral sclerosis. Exp Neurol 213:229–237CrossRefGoogle Scholar
  24. 24.
    Shishido Y, Furushiro M, Hashimoto S, Yokokura T (2001) Effect of nordihydroguaiaretic acid on behavioral impairment and neuronal cell death after forebrain ischemia. Pharmacol Biochem Behav 69:469–474CrossRefGoogle Scholar
  25. 25.
    Majumdar DK, Govil JN, Singh VK (2003) Recent progress in medicinal plants. Vol 8 Phytochemistry and Pharmacology. Studium, Houston, TXGoogle Scholar
  26. 26.
    Ellman GL, Courtney KD, Andres V Jr, Featherstone RM (1961) Biochem Pharmacol 7:88–95CrossRefGoogle Scholar
  27. 27.
    Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, Silman I (1991) Science 253:872–879CrossRefGoogle Scholar
  28. 28.
    Bon S, Vigny M, Massoulie J (1979) Asymmetric and globular forms of acetylcholinesterase in mammals and birds. Proc Natl Acad Sci USA 76:2546–2550CrossRefGoogle Scholar
  29. 29.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26CrossRefGoogle Scholar
  30. 30.
    Ekins S, Waller CL, Swann PW, Cruciani G, Wrighton SA, Wikel JH (2000) J Pharmacol Toxicol 44:251–272CrossRefGoogle Scholar
  31. 31.
    Alavijeh MS, Chishty M, Qaiser MZ, Palmer AM (2005) Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery. NeuroRx 2:554–571Google Scholar
  32. 32.
    Clark DE (2003) In silico prediction of blood–brain barrier permeation. Drug Discov Today 8:927–933CrossRefGoogle Scholar
  33. 33.
    Lloyd EJ, Andrews PR (1986) A common structural model for central nervous system drugs and their receptors. J Med Chem 29:453–462CrossRefGoogle Scholar
  34. 34.
    Lemke TL, Williams DA, Roche VF, Zito SW (2008), Foye’s principles of medicinal chemistry. Wolters Kluwer/Lippincott Williams and Wilkins, BaltimoreGoogle Scholar
  35. 35.
    Pajouhesh H, Lenz GR (2005) Medicinal chemical properties of successful central nervous system drugs. NeuroRx 2:541–553CrossRefGoogle Scholar
  36. 36.
    Clark DE (1999) Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 2. Prediction of blood–brain barrier penetration. J Pharm Sci 88:815–821CrossRefGoogle Scholar
  37. 37.
    Ajay, Bemis GW, Murcko MA (1999) Designing libraries with CNS activity. J Med Chem 42:4942–4951CrossRefGoogle Scholar
  38. 38.
    Balon K, Riebesehl BU, Muller BW (1999) Determination of liposome partitioning of ionizable drugs by titration. J Pharm Sci 88:802–806CrossRefGoogle Scholar
  39. 39.
    Bhal SK, Kassam K, Peirson IG, Pearl GM (2007) The rule of five revisited: applying log d in place of log p in drug-likeness filters. Mol Pharmaceut 4:556–560CrossRefGoogle Scholar
  40. 40.
    Garberg P, Ball M, Borg N, Cecchelli R, Fenart L, Hurst RD, Lindmark T, Mabondzo A, Nilsson JE, Raub TJ, Stanimirovic D, Terasaki T, Oberg JO (2005) In vitro models for the blood–brain barrier. Toxicol In Vitro 19:299–334CrossRefGoogle Scholar
  41. 41.
    Deli MA, Abraham CS, Kataoka Y, Niwa M (2005) Permeability studies on in vitro blood–brain barrier models: physiology, pathology, and pharmacology. Cell Mol Neurobiol 25:59–127CrossRefGoogle Scholar
  42. 42.
    Reichel A, Begley DJ, Abbott NJ (2003) An overview of in vitro techniques for blood–brain barrier studies. Methods Mol Med 89:307–324Google Scholar
  43. 43.
    Doan KM, Humphreys JE, Webster LO, Wring SA, Shampine LJ, Serabjit-Singh CJ (2002) Passive permeability and P-glycoproteinmediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J Pharmacol Exp Ther 303:1029–1037CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Chandran Remya
    • 1
  • Kalarickal Vijayan Dileep
    • 1
  • Ignatius Tintu
    • 1
  • Elessery Jayadevi Variyar
    • 1
  • Chittalakkottu Sadasivan
    • 1
  1. 1.Department of Biotechnology and Microbiology and Inter University Centre for BiosciencesKannur UniversityKeralaIndia

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